The evidence from family, twin, and adoption studies has established that the risk for developing schizophrenia involves a substantial genetic component (McGuffin, Farmer, and Gottesman, 1987). The major challenge now confronting researchers is to determine the mode or modes of genetic transmission. Advances in the last decade in recombinant DNA technology, especially improvements in methods for generating and isolating restriction fragment length polymorphisms (RFLPs), have made it possible to use DNA sequence polymorphisms to trace alleles at specific genomic loci. The power of these methods have recently been demonstrated by two landmark studies (Barrett et al., 1988; Sherrington et al., 1988) providing the first evidence for genetic linkage in schizophrenia. These findings foreshadow a series of breakthroughs in clarifying the etiology and pathophysiology of schizophrenia. The major objective of this proposed Diagnostic Center is to work as one of three centers in developing a sample of 200 multiplex schizophrenic families for subsequent linkage studies. To this end, approximately 67 families will be recruited from a Harvard Medical School consortium of hospitals from the 6-month to the 4 1/2 year period of a 5-year contract. Families will be sought with two or more affected siblings and an average of seven first-degree relatives, including both parents. More two- generation families. Selected probands and relatives will receive extensive assessment using state of the art tools in psychiatric epidemiology and neuropsychology. Blood samples will also be obtained from all subjects for transformation into lymphoblast cell lines for subsequent linkage analyses. The principal hypothesis of this study is that a major gene or genes contributes to the etiology of this disorder, which can be identified through genetic linkage analysis of a well-defined sample of multiplex families. The key question is whether there are specific DNA markers which co-segregate with the disease trait. Linkage analyses of our center sample will focus first on the chromosome 5 region where linkage has been shown as well on DNA markers linked to loci implicated in catecholamine metabolism.